1. Field of the Invention
The present invention relates to conjugates of biologically active compounds, preferably therapeutically active compounds, with polymeric moieties having low polydispersity, as well as controlled polymerisation processes for producing the conjugates.
2. Description of the Related Art
The field of polymer therapeutics involves provision of conjugates of therapeutically active compounds and polymers of various types. Selection of the class of polymer, and its properties, allows control of delivery of the therapeutic to a target within the body of the patient to be treated. Targeting may be active, by providing the conjugate with a specific label, capable of binding to complementary molecules in the target region, or passive, by controlling the molecular weight of the polymer. Conjugation of a therapeutically active compound to a polymer may control the solubility of the therapeutically active compound, its stability in the circulation, its rate of removal by the kidneys and/or liver, as well as its immunogenicity.
One example of a polymer therapeutic is the compound PK-1, a conjugate of doxorubicin with hydroxypropylmethacrylamide copolymer. The drug is conjugated to side chains on the polymer by an oligopeptidyl linker.
In WO-A 01/18080, controlled radical polymerisation processes are used to form the polymers from monomers having reactive groups, which may, after polymerisation, be used to conjugate to therapeutic ligands. The low polydispersity polymers formed by the controlled radical polymerisation processes are said to have particular advantages for therapeutic use.
Non-polymeric groups may also be conjugated to biologically active molecules, for instance therapeutically active molecules, to increase their water solubility, as well as control their stability in serum/circulation, especially for controlling drug delivery for orally administered compounds. In WO-A 98/43676, U.S. Pat. Nos. 5,888,990 and 6,127,349, a variety of therapeutically active compounds, including compounds which are water-insoluble, are conjugated to zwitterionic groups, to control their solubility or stability in serum. The zwitterionic groups may be phosphocholine groups. The synthetic method for conjugating the phosphocholine groups generally involves reaction of an alcohol with 2-chloro-2-oxo-1,3,2-dioxaphospholane, followed by a ring opening amination with trimethylamine. Other reactions involve conjugation of an alcohol having a PC group, with the carboxylic group of a therapeutically active using a carbodiimide to form an ester conjugate.
In our earlier publication WO-A 93/15775, ethylenically unsaturated monomers including zwitterionic groups, for instance 2-methacryloyloxy-2′-ethyltrimethylammoniumphosphate inner salt (MPC), are polymerised by a graft polymerisation process onto carbohydrate substrates. The substrate may be soluble, for instance a water soluble cellulose derivative. Polymerisation involves generation of a free radical at a hydroxyl group on the substrate by contact with cerium IV ions. The zwitterionic treated compounds were then used at surfaces of membranes to improve haemocompatibility.
In our earlier application, not published at the priority date hereof, PCT/GB01/04432, atom transfer radical polymerisation is carried out using monomers including zwitterionic monomers, for instance MPC. The product polymers may be used as matrices for drug delivery, for instance block copolymers may form micelles, useful as drug delivery vehicles. There is no suggestion that covalent conjugation of the drug molecule to the polymer should be considered.
Haddleton, in a paper presented at a meeting of the Society Chemical Industry London 1999, describes atom transfer radical polymerisation using initiators comprising biologically active molecules including carbohydrates, especially ribose moieties of nucleosides or steroids. The monomers are ethylenically unsaturated monomers which may form water soluble products. The monomers may include polyethylene glycol moieties (polyethyleneglycol methacrylate), as well as cationic groups, such as acrylic ester compounds having amine substituents in the alkyl groups. Suitable initiators are formed by acylating an alcohol derivative of the biologically active molecule with a reactive acid compound having an a halogen substituent, preferably at a tertiary carbon atom.